JP2018070535A - Active ingredient-containing particles, formulations, topical agents, cosmetics, and injections - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide active ingredient-containing particles which are excellent in the in vivo absorption properties of an active ingredient.SOLUTION: The present invention provides an active ingredient-containing particle having a particle body containing an active ingredient, and a coating layer which coats at least one portion of the surface of the particle body and contains a surfactant, the particle body being a solid, and the affinity index X represented by the following formula (1) ranging in 0.05<X<0.2. X=S-S...(1) [In the formula (1), Srepresents a scattering vector q(nm) in the maximum value of scattering intensity, in the scattering profile obtained by the small-angle X-ray scattering of the active ingredient-containing particle at the measurement temperature of 25°C; and Srepresents the scattering vector q(nm) in the maximum value of scattering intensity, in the scattering profile obtained by the small-angle X-ray scattering of the surfactant at the measurement temperature of 25°C.]SELECTED DRAWING: None

Description

  The present invention relates to active ingredient-containing particles, and preparations, external preparations, cosmetics and injections containing the active ingredient-containing particles.

  Various techniques have been proposed to improve the absorption of active ingredients into the body. For example, in Patent Documents 1 and 2, a preparation using particles (active ingredient-containing particles) formed by combining a phase containing a hydrophilic active ingredient and a phase containing a surfactant to form an aggregate, so-called S / O (Solid in Oil) formulations are disclosed. In this S / O (Solid in Oil) formulation, it is possible to control the pharmacokinetics of an active ingredient while improving the absorbability of the active ingredient into the body by a surfactant.

Japanese Patent No. 4334939 Japanese Patent No. 4844494

  The present inventors have been analyzing the active ingredient-containing particles, and even if the active ingredient is made into particles with a surfactant, the absorbability into the body is not improved or the absorbability into the body is reduced. Found that there is a case.

  The objective of this invention is providing the active ingredient containing particle | grains which are excellent in the absorptivity in the body of an active ingredient, the formulation containing this active ingredient containing particle | grain, external preparation, cosmetics, and an injection.

  As a result of intensive studies to solve the above problems, the present inventors have found that the affinity between the active ingredient and the surfactant in the active ingredient-containing particle varies depending on the particle, and further, this affinity is absorbed into the body. I found that I was involved in sex. Furthermore, as a result of further research, the inventors have found an affinity parameter associated with absorbability into the body, and found that if this is within a certain range, the absorbability into the body can be further increased. The present invention has been completed through further trial and error based on this finding, and includes the following aspects.

  The active ingredient-containing particles according to the present invention include a particle main body containing an active ingredient, and a coating layer that covers at least a part of the surface of the particle main body and contains a surfactant. The main body is solid, and the affinity index X represented by the following formula (1) is in the range of 0.05 <X <0.2.

X = S ₀ −S ₁ (1)

Wherein (1), S _1, in a scattering profile obtained by small-angle X-ray scattering at measurement temperature 25 ° C. of the active ingredient-containing particles, indicates the scattering vector q at the maximum value of scattering intensity (nm ^-1) , S ₀ represents a scattering vector q (nm ⁻¹ ) at the maximum value of the scattering intensity in a scattering profile obtained by small-angle X-ray scattering at a measurement temperature of 25 ° C. of the surfactant. ]

  The active ingredient-containing particles according to the present invention preferably have a core-shell structure in which the particle main body is a core portion and the coating layer is a shell portion.

In the active ingredient-containing particles according to the present invention, preferably, the scattering vector q at the maximum value of the active ingredient-containing particles and the surfactant is in the range of 1.0 to 3.0 nm ⁻¹ , respectively.

  The preparation of the present invention contains particles containing active ingredients constituted according to the present invention.

  In the preparation of the present invention, the weight ratio of the active ingredient to the surfactant (active ingredient weight: surfactant weight) is preferably in the range of 1: 5 to 1: 100.

  The external preparation of the present invention includes a preparation constituted according to the present invention.

  The cosmetic product of the present invention comprises a formulation constructed according to the present invention.

  The injection of the present invention includes a preparation constituted according to the present invention.

  ADVANTAGE OF THE INVENTION According to this invention, the active ingredient containing particle | grains which are excellent in the absorptivity in the body of an active ingredient can be provided.

The scattering profile of the particle | grains of Examples 1-2 and sucrose erucic acid ester (ER-290) obtained by the small angle X-ray scattering analysis of Test Example 1 is shown. The scattering profile of the particle | grains of Comparative Examples 1-2 and the sucrose erucic acid ester (ER-290) obtained by the small angle X-ray scattering analysis of Test Example 1 is shown. The scattering profile of the particle | grains of Comparative Examples 3-5 and the sucrose erucic acid ester (ER-290) obtained by the small angle X-ray scattering analysis of Test Example 1 is shown. 6 is a simplified diagram of a drug skin permeation test cell used in Test Example 2. FIG. 10 is a plot graph showing the results of Test Example 2.

  Details of the present invention will be described below.

  In the present specification, the expression “containing” includes the concepts of “including”, “consisting essentially of”, and “consisting only of”.

  In the present specification, “absorbability (to the body)” means, for example, “percutaneous absorbability (skin permeability)”, “absorbance other than through the skin, for example, eye drops, nasal passage, intravaginal, It encompasses the concept of “absorption via the rectum (suppository), subcutaneous, intradermal, intramuscular”.

1. Active ingredient-containing particles The active ingredient-containing particles of the present invention (sometimes referred to as “particles”) of the present invention contain an active ingredient and are solid, a particle body, and a surfactant. And an affinity index X represented by the following formula (1) is in a range of 0.05 <X <0.2.

X = S ₀ −S ₁ (1)

  The particle body and the coating layer may be connected to each other to form an aggregate. It is preferable that they are connected by intermolecular force to form an aggregate. In the particles of the present invention, it is preferable that part or all of the surface of the particle main body is covered with a coating layer from the viewpoints of absorption and sustained release of the active ingredient. Preferably 30% or more, more preferably 50% or more, further preferably 70% or more, more preferably 85% or more, still more preferably 95% or more, particularly preferably 99% or more of the surface of the particle body depends on the coating layer. It is desirable to be coated directly or indirectly. The surface of the particle body is preferably directly coated with a coating layer. As an example of the aspect of the particle, there is a core-shell structure in which the particle main body corresponds to the core portion and the coating layer corresponds to the shell portion including the core portion.

In formula (1), definitions of S ₀ and S ₁ are as follows.

S ₁ represents a scattering vector q (nm ⁻¹ ) at the maximum value of the scattering intensity in a scattering profile obtained by small-angle X-ray scattering at a measurement temperature of 25 ° C. of the active ingredient-containing particles.

S ₀ represents a scattering vector q (nm ⁻¹ ) at the maximum value of the scattering intensity in a scattering profile obtained by small-angle X-ray scattering at a measurement temperature of 25 ° C. of the surfactant.

The scattering profile is obtained by irradiating a sample with X-rays and, based on data acquired by detecting the position and intensity of the scattered X-rays with a detector, the scattering intensity I (q) with respect to the scattering vector q. It is a two-dimensional graph obtained by plotting. Typically, it is a two-dimensional graph in which the horizontal axis represents the magnitude of the scattering vector q (nm ⁻¹ ) and the vertical axis represents the scattering intensity I. The sample is, for example, a sample made of active ingredient-containing particles or a sample made of a surfactant. The scattering vector q (nm ⁻¹ ) is q = (4π / λ) sin (θ / 2) (λ is the wavelength of the X-ray and θ is the scattering angle). A typical scattering profile of a sample composed of particles containing active ingredients and a sample composed of a surfactant is illustrated in FIG. But FIG. 1 has shown the scattering profile of the particle | grains of Examples 1-2 and sucrose erucic acid ester (ER-290) obtained by the small angle X-ray scattering analysis of Test Example 1 mentioned later.

  The scattering profile contains information about the microstructure of the sample. For example, the distance between the molecules of the sample molecule can be known from the scattering vector q at the maximum value of the scattering intensity. The scattering vector q at the maximum value is on the lower angle side (low q side), indicating that the distance between the sample molecules is longer. When the scattering vector q at the maximum value of the scattering intensity derived from the surfactant of the active ingredient-containing particles is shifted to the low angle side with respect to the scattering vector q at the maximum value of the scattering intensity of the surfactant, It shows that the distance between the surfactant molecules in the particles is increased. In particular, when the affinity between the active ingredient molecule and the surfactant molecule in the particle is high, the active ingredient molecule can exist between the surfactant molecules, and as a result, the distance between the surfactant molecules becomes longer. That is, when the scattering vector q at the maximum value of the scattering intensity derived from the surfactant of the particles is shifted to the low angle side with respect to the scattering vector q at the maximum value of the scattering intensity of the surfactant, the effective component and the interface It shows that the affinity of the active agent is high. The above information can be acquired by analyzing the scattering profile.

  The X-ray source is not particularly limited, and synchrotron radiation X-rays and rotating Cu cathode characteristic X-rays can be used. Of these, synchrotron radiation X-rays are preferably used.

  The synchrotron radiation is light emitted synchrotron along with the electron synchrotron. Synchrotron radiation includes electromagnetic waves of various wavelengths having characteristics such as single color, high luminance, and high directivity, and the X-ray region also includes single color, high luminance, or high directivity X-rays. It is out. Therefore, by using this X-ray, it is possible to acquire a scattering profile including more information than when using a normal X-ray using an X-ray tube or the like.

  Such synchrotron radiation includes, for example, SPring-8 of the High Brightness Optical Science Research Center, PF ring of the High Energy Accelerator Research Organization, UVSOR of the Molecular Science Research Institute, HiSOR of the Hiroshima University Synchrotron Radiation Research Center, etc. It can be measured at a synchrotron radiation facility.

  Detection and data analysis can be performed using an apparatus generally used conventionally in the small-angle X-ray scattering method.

The scattering vector q at the maximum value of the scattering intensity is a point at which the change of the scattering intensity I starts from increasing to decreasing when the scattering profile I changes from the smaller side of the scattering vector q in the scattering profile (in FIG. 1). , For example, the scattering vector q at the point indicated by the arrow A). The maximum value usually appears when the scattering vector q is 1.0 or more. From the viewpoint that the effects of the present invention can be more reliably exhibited, the scattering vector q indicating the maximum value of the scattering intensity is preferably in the range of 1.0 to 3.0 nm ⁻¹ . In addition, when two or more local maximum values exist, it is preferable to employ the largest local maximum value among them. When the active ingredient is crystallized, a specific peak indicating a crystalline state appears in a relatively high angle region, for example, q ≧ 4.0, but this peak is not included in the maximum value.

The surfactant of “scattering profile obtained by small-angle X-ray scattering at a measurement temperature of 25 ° C. of surfactant” in the definition of S ₀ and “measurement temperature of particles containing active ingredients at 25 ° C.” in the definition of S ₁ It may be different from the surfactant constituting the active ingredient-containing particles of the “scattering profile obtained by small-angle X-ray scattering”. But it is preferable that it is the same from a viewpoint that the effect of this invention can be exhibited still more reliably. That is, when the former surfactant is surfactant A, the latter surfactant is also preferably surfactant A.

  The affinity index X is the difference between the scattering vector q at the maximum value of the scattering intensity of the surfactant and the scattering vector q at the maximum value of the scattering intensity of the active ingredient-containing particles. Therefore, when the affinity index X is high, it is considered that it means that the affinity between the active ingredient molecule and the surfactant molecule in the active ingredient-containing particle is further improved.

  In the present invention, the affinity index X is less than 0.2. From the viewpoint that the effects of the present invention can be more reliably exhibited, the affinity index X is preferably 0.19 or less, more preferably 0.18 or less, and still more preferably 0.17.

  The affinity index X is greater than 0.05. From the viewpoint that the effects of the present invention can be more reliably exhibited, it is preferably 0.06 or more, more preferably 0.07 or more, and still more preferably 0.08 or more.

  The number average particle diameter of the particles of the present invention is not particularly limited. The number average particle diameter of the particles is, for example, 1 nm to 500 nm, preferably 1 nm to 100 nm, more preferably 1 nm to 50 nm.

  In the present invention, the number average particle diameter of the particles is a number average diameter calculated by a dynamic light scattering method when a solvent (for example, squalane or the like) is dispersed.

  The shape of the particles is not particularly limited. Examples of the particle shape include a spherical shape, a rod shape, a cubic shape, a lens shape, and a sea urchin shape.

  The water content of the particles is preferably 20% by weight or less, more preferably 10% by weight or less, more preferably 5% by weight or less, particularly preferably 1% by weight or less, most preferably the particles are substantially free of moisture. . That is, the active ingredient-containing particles of the present invention are different from the particles in the W / O emulsion.

1.1. Particle Body In the present invention, the particle body is a solid. Since the particle body is solid, the stability in the base described later is further improved. Therefore, a formulation having an S / O (Solid in Oil) type structure can be formed by dispersing the active ingredient-containing particles in a base phase that is an oil phase.

  In the present invention, the particle body contains at least an active ingredient.

  The active ingredient is not particularly limited as long as it is a physiologically active ingredient. Preferably, it is a component blended for the purpose of exerting its physiological activity. As an active ingredient, the ingredient mix | blended as an active ingredient in a pharmaceutical, cosmetics, etc. is mentioned, for example. Since many active ingredients of pharmaceuticals and cosmetics are organic substances, the active ingredients may be organic substances. The active ingredient is preferably a solid.

  As an active ingredient blended in a pharmaceutical, any of those requiring a systemic action and those requiring a local action can be used.

  Specific examples of the active ingredient included in the pharmaceutical are not particularly limited, for example, dementia therapeutics, antiepileptic drugs, antidepressants, antiparkinsonian drugs, antiallergic drugs, anticancer drugs, diabetes therapeutic drugs, antihypertensive drugs, Examples thereof include ED therapeutic agents, skin disease agents, local anesthetics, peptide drugs, or pharmaceutically acceptable salts thereof. More specifically, memantine, donepezil, diphenhydramine, vardenafil, octreotide, rivastigmine, galantamine, nitroglycerin, lidocaine, fentanyl, male hormones, female hormones, nicotine, clomipramine, nalfurafine, metoprolol, fesoterodine, vardenafil, nalfurfine, tandolone , Beraprost sodium, tartilellin, lurasidone, nefazodone, rifaximin, benidipine, doxazosin, nicardipine, formoterol, lomerizine, amlodipine, teriparatide, bucladecin, cromoglycic acid, lixenatide, exenatide, liraglutitonin, lanreotide gluconide Risedronic acid Diclofenac, or ascorbic acid or acceptable salts on these pharmaceutical thereof.

  The pharmaceutically acceptable salt is not particularly limited, and any of an acidic salt and a basic salt can be employed. Examples of acid salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, propionate, tartrate, fumarate, maleate, malic acid Organic salts such as salts, citrates, methanesulfonates, benzenesulfonates or paratoluenesulfonates. Examples of basic salts include alkali metal salts such as sodium salts and potassium salts, or alkaline earth metal salts such as calcium salts and magnesium salts. Specific active ingredient salts include, for example, memantine hydrochloride, donepezil hydrochloride, rivastigmine tartrate, galantamine hydrobromide, clomipramine hydrochloride, diphenhydramine hydrochloride, nalfrafin hydrochloride, metoprolol tartrate, fesoterodine fumarate , Vardenafil hydrochloride hydrate, nalfrafin hydrochloride, tandospirone citrate, beraprost sodium, lurasidone hydrochloride, nefazodone hydrochloride, benidipine hydrochloride, doxazosin mesylate, nicardipine hydrochloride, formoterol fumarate, romeridine hydrochloride, Or amlodipine besylate is exemplified.

  The active ingredient blended in the cosmetic is not particularly limited as long as skin permeation is required. For example, vitamin ingredients such as vitamin C and vitamin E, moisturizing ingredients such as hyaluronic acid, ceramide and collagen, tranexamic acid, Whitening ingredients such as arbutin, hair growth ingredients such as minoxidil, cosmetic ingredients such as FGF (fibroblast growth factor) and EGF (epidermal growth factor), or salts and derivatives thereof.

  From the viewpoint that the effects of the present invention can be more reliably exhibited, the active ingredient is preferably an acidic salt or a basic salt. In this case, the acid salt is preferably an inorganic acid salt.

  As an active ingredient, a hydrophilic thing is preferable.

  When the active ingredient is hydrophilic, it is not particularly limited, but it is preferable that the molecular weight is 10,000 or less and the octanol water partition coefficient is -6 to 6.

  The molecular weight is preferably 5000 or less, more preferably 2000 or less, and still more preferably 1000 or less. Although the minimum of molecular weight is not specifically limited, Usually, it is 50.

  The octanol water partition coefficient is preferably -6 to 5, more preferably -6 to 3, and further preferably -5 to 3, from the viewpoint that the effects of the present invention can be more reliably exhibited. .

  In the present invention, the octanol water partition coefficient can be calculated by the following formula from the drug concentration of each phase after adding the drug into a flask containing octanol and an aqueous buffer solution of pH 7 after shaking. .

Octanol water partition coefficient = Log ₁₀ (Drug concentration in octanol phase / Drug concentration in water phase)

  The amount of the active ingredient contained in the particles of the present invention depends on the type of the active ingredient, but is, for example, 0.1 to 30% by weight (based on the total weight of all the raw materials contained in the particles) ).

  An active ingredient can also be used independently and can also be used in combination of arbitrary 2 or more types.

  The particle body may further contain at least one other component in addition to the active component. Although it does not specifically limit as another component, For example, a stabilizer, an absorption promoter, an irritation | stimulation reducing agent, or an antiseptic | preservative etc. are mentioned.

  The stabilizer has a function of stabilizing the particle structure, prevents unintended early collapse of the particle structure, and has a role of ensuring a sustained release effect of the active ingredient.

  Although it does not specifically limit as a stabilizer, Specifically, polysaccharide, protein, a hydrophilic polymer material, etc. are mentioned. A stabilizer may contain 1 type, or 2 or more types. The content of the stabilizer in the particle body can be appropriately set depending on the type of the stabilizer. For example, the stabilizer is blended so that the weight ratio of the active ingredient and the stabilizer is 1: 0.1 to 1:10. Can do.

  Although it does not specifically limit as an absorption promoter, Specifically, higher alcohol, N-acyl sarcosine or its salt, higher monocarboxylic acid, higher monocarboxylic acid ester, aromatic monoterpene fatty acid ester, C2-C10 Or a salt thereof, polyoxyethylene alkyl ether phosphate ester or salt thereof, lactic acid, lactic acid ester, or citric acid. The absorption promoter may contain 1 type (s) or 2 or more types. The content of the absorption accelerator in the particle body can be appropriately set depending on the type of the absorption accelerator. For example, the weight ratio of the active ingredient and the absorption accelerator is 1: 0.01 to 1:50. Can do.

  The irritation reducing agent is not particularly limited, but specifically, hydroquinone glycoside, pantethine, tranexamic acid, lecithin, titanium oxide, aluminum hydroxide, sodium nitrite, sodium hydrogen nitrite, soybean lecithin, methionine, glycyrrhetin Examples include acid, BHT, BHA, vitamin E or a derivative thereof, vitamin C or a derivative thereof, benzotriazole, propyl gallate, or mercaptobenzimidazole. The irritation reducing agent may contain one kind or two or more kinds. The content ratio of the irritation reducing agent in the particle body can be appropriately set depending on the type, but can be blended so as to be, for example, 0.1 wt% to 50 wt%.

  The preservative is not particularly limited, and specific examples include methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol, and thymol. The content ratio of the preservative in the particle main body can be appropriately set depending on the kind of the preservative, but for example, it can be blended so as to be 0.01 wt% to 10 wt%. An antiseptic | preservative may contain 1 type (s) or 2 or more types.

1.2. Coating layer The coating layer contains at least a surfactant.

  As the surfactant, those having a weighted average value of HLB values of 10 or less, preferably 8 or less, more preferably 7 or less can be used.

  The HLB (Hydrophile Lyophile Balance) value in the present invention is an index for knowing whether an emulsifier is hydrophilic or lipophilic, and takes a value of 0 to 20. It shows that lipophilicity is so strong that an HLB value is small. In the present invention, the HLB value is calculated from the following Griffin equation.

  HLB value = 20 × {(molecular weight of hydrophilic portion) / (total molecular weight)}

  The weighted average value of the HLB value is calculated as follows.

  For example, when there are surfactant raw materials having HLB values A, B, and C, and the charged weights at the time of synthesis of the respective particles are x, y, and z, the calculation formula of the weighted average value is (xA + yB + zC) / (x + y + z) ).

  The surfactant is not particularly limited and can be appropriately selected depending on the application. For example, it can be widely selected from those that can be used as pharmaceuticals and cosmetics. A plurality of types of surfactants may be used in combination.

  The surfactant may be any of a nonionic surfactant, an anionic surfactant, a cationic surfactant, and an amphoteric surfactant.

  The nonionic surfactant is not particularly limited, and examples thereof include fatty acid esters, fatty alcohol ethoxylates, polyoxyethylene alkyl phenyl ethers, alkyl glycosides or fatty acid alkanolamides, or polyoxyethylene castor oil or hydrogenated castor oil. Can be mentioned.

  The fatty acid ester is not particularly limited, but a sugar fatty acid ester is preferable. Specific examples include esters of fatty acids such as erucic acid, oleic acid, lauric acid, stearic acid or behenic acid and sugar. As the sugar, sucrose is preferable.

  The other fatty acid ester is not particularly limited, and examples thereof include an ester of glycerin, polyglycerin, polyoxyethylene glycerin, sorbitan, or polyoxyethylene sorbit with a fatty acid.

  Examples of the anionic surfactant include alkyl sulfate ester salts, polyoxyethylene alkyl ether sulfate ester salts, alkylbenzene sulfonate salts, fatty acid salts, and phosphate ester salts.

  Examples of the cationic surfactant include alkyl trimethyl ammonium salts, dialkyl dimethyl ammonium salts, alkyl dimethyl benzyl ammonium salts, and amine salts.

  Examples of amphoteric surfactants include alkylamino fatty acid salts, alkylbetaines, and alkylamine oxides.

  As the surfactant, sucrose fatty acid ester, glycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbite fatty acid ester, polyoxyethylene castor oil or hydrogenated castor oil is particularly preferably used.

  The surfactant may have a hydrocarbon chain such as an alkyl chain, an alkenyl chain, or an alkynyl chain. The hydrocarbon chain length is not particularly limited, but can be selected widely from 5 to 30 carbon atoms on the main chain, and particularly preferably 6 to 24.

  Surfactant can also be used independently and can also be used in combination of arbitrary 2 or more types.

  The coating layer may further contain at least one other component in addition to the surfactant.

  Although it does not specifically limit as another component, For example, an irritation | stimulation reducing agent, an analgesic agent, an absorption promoter, a stabilizer, or antiseptic | preservative etc. are mentioned.

  The irritation reducing agent is not particularly limited, but specifically, hydroquinone glycoside, pantethine, tranexamic acid, lecithin, titanium oxide, aluminum hydroxide, sodium nitrite, sodium hydrogen nitrite, soybean lecithin, methionine, glycyrrhetin Examples thereof include acids, BHT, BHA, vitamin E and derivatives thereof, vitamin C and derivatives thereof, benzotriazole, propyl gallate, and mercaptobenzimidazole. The irritation reducing agent may contain one kind or two or more kinds. Although the content rate in the coating layer of the irritation reducing agent can be appropriately set depending on the type, for example, it can be blended so as to be 0.1 wt% to 50 wt%.

  Although it does not specifically limit as an analgesic, Specifically, local anesthetics, such as procaine, tetracaine, lidocaine, dibucaine, or prilocaine, its salt, etc. are mentioned. An analgesic may contain 1 type (s) or 2 or more types. Although the content rate in the coating layer of an analgesic can be suitably set also according to the kind, it can mix | blend so that it may become 0.1 to 30 weight%, for example.

  Although it does not specifically limit as an absorption promoter, Specifically, higher alcohol, N-acyl sarcosine or its salt, higher monocarboxylic acid, higher monocarboxylic acid ester, aromatic monoterpene fatty acid ester, C2-C10 Or a salt thereof, polyoxyethylene alkyl ether phosphate ester or salt thereof, lactic acid, lactic acid ester, or citric acid. The absorption promoter may contain 1 type (s) or 2 or more types. The content ratio of the absorption accelerator in the coating layer can be set as appropriate depending on the type of the absorption accelerator, but for example, it can be blended so as to be 0.1 wt% to 30 wt%.

  When the particles have a core-shell structure, the stabilizer has an action of stabilizing the core-shell structure, prevents unintended early disintegration of the core-shell structure, and ensures the sustained release effect of the active ingredient. .

  The stabilizer is not particularly limited, and specifically, fatty acids or salts thereof, parahydroxybenzoates such as methylparaben and propylparaben, alcohols such as chlorobutanol, pendyl alcohol, and phenylethyl alcohol, thimerosal , Acetic anhydride, sorbic acid, sodium bisulfite, L-ascorbic acid, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate, tocopherol acetate, dl-α-tocopherol, protein or polysaccharide.

  A stabilizer may contain 1 type, or 2 or more types. The content of the stabilizer in the coating layer can be appropriately set depending on the type. For example, when the surfactant is a sucrose fatty acid ester, the weight ratio of the sucrose fatty acid ester to the stabilizer is 1 : It can also mix | blend so that it may be set to 0.01-1: 50.

  The preservative is not particularly limited, and specific examples include methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol, and thymol. An antiseptic | preservative may contain 1 type (s) or 2 or more types. The content ratio of the preservative in the coating layer can be set as appropriate depending on the type of the preservative, but for example, it can be blended so as to be 0.01 wt% to 10 wt%.

2. Formulation The formulation of the present invention contains at least the active ingredient-containing particles (particles) of the present invention.

  The content ratio of the particles in the preparation is not particularly limited, but in the case of a patch, ointment, cream or gel, it is preferably 10% by weight or more and 70% by weight or less, more preferably 20% by weight or more. 50% by weight or less.

  In the preparation of the present invention, the weight ratio between the active ingredient and the surfactant (active ingredient weight: surfactant weight) can be appropriately set within the range where the effects of the present invention are exhibited. 3 to 1: 100. From the viewpoint that the effects of the present invention can be more reliably exhibited, the weight ratio is preferably 1: 5 to 1: 100, more preferably 1: 5 to 1:70, and 1: 5 to 1. : 50 is more preferable, 1: 5 to 1:40 is particularly preferable, and 1: 5 to 1:35 is most preferable.

  The preparation of the present invention is a preparation intended for percutaneous absorption or transmucosal absorption of cosmetics, etc. according to the type of active ingredient, for example, external preparations such as topical skin preparations, eye drops, nasal drops, suppositories, oral medicines, Or it can be used for wide uses, such as an injection.

  Although the formulation of the present invention is not particularly limited, it is usually sustained for 1 day to 1 week, and in a preferred embodiment, it is used so as to be applied once a day to 1 week.

  When the preparation of the present invention is an external medicine, the target disease varies depending on the type of active ingredient.

  The preparation of the present invention is not particularly limited, and is a tape agent (reservoir type, matrix type, etc.) such as a plaster or plaster, a patch, patch, microneedle or other patch, ointment, liniment or lotion. Used as external liquids such as topical aerosols, sprays such as external aerosols or pump sprays, creams, gels, eye drops, eye ointments, nasal drops, suppositories, rectal semisolids or enemas it can.

  The preparation of the present invention preferably has a water content of 20% by weight or less, and more preferably contains substantially no water. Thereby, it is possible to further improve the shape-retaining property of the particles of the present invention, and it is possible to further suppress the leakage of the active ingredient from the particles and thus the crystallization of the active ingredient. As a result, even higher absorbability can be exhibited. From this viewpoint, the preparation of the present invention is preferably used for an agent whose water content is adjusted to 20% by weight or less, and more preferably used for an agent containing substantially no water. Specifically, the preparation of the present invention is preferably used as, for example, a plaster, patch, ointment, gel or the like.

2.1. Base Phase The preparation of the present invention may further contain a phase (base phase) containing a base, and the base phase may contain particles. At this time, the particles are preferably dispersed or dissolved in the base phase.

  The base is not particularly limited, and can be selected from a wide range of drugs that can be used as pharmaceuticals and cosmetics such as external drugs.

  As described above, the particles of the present invention have a solid particle body. Therefore, when the base phase is an oil phase, an S / O (Solid in Oil) type preparation can be formed by dispersing the particles in the base phase that is the oil phase. The S / O type preparation can be obtained, for example, by dispersing particles obtained by a production method described later in an oil phase.

  The base can be appropriately selected from those suitable for dispersing or dissolving the particles according to the purpose of use, and is not particularly limited.

  A plurality of types of bases may be used in combination.

  The base is not particularly limited, and examples thereof include an oily base and an aqueous base. Examples of the oil base include elastomers, vegetable oils, animal oils, neutral lipids, synthetic fats and oils, sterol derivatives, waxes, hydrocarbons, monoalcohol carboxylic acid esters, oxyacid esters, polyhydric alcohol fatty acid esters, Examples include silicones, higher alcohols, higher fatty acids, and fluorine-based oils. Examples of the aqueous base include water and (polyhydric) alcohol.

  The elastomer is not particularly limited, but styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), styrene-ethylene-butylene-styrene block copolymer (SEBS), Examples thereof include rubber-based rubbers such as polyisobutylene (PIB) and isoprene rubber (IR), silicone-based rubbers such as silicone rubber, and urethane-based elastomers.

  The vegetable oil is not particularly limited, and examples thereof include soybean oil, sesame oil, olive oil, palm oil, balm oil, rice bran oil, cottonseed oil, sunflower oil, rice bran oil, cacao butter, corn oil, bean flower oil, castor oil or rapeseed oil. Can be mentioned.

  Although it does not specifically limit as animal oil, For example, mink oil, turtle oil, fish oil, cow oil, horse oil, pig oil, shark squalane, etc. are mentioned.

  The neutral lipid is not particularly limited, and examples thereof include triolein, trilinolein, trimyristin, tristearin, and triarachidonin.

  Although it does not specifically limit as synthetic fats and oils, For example, a phospholipid or an azone etc. are mentioned.

  The sterol derivative is not particularly limited, and examples thereof include dihydrocholesterol, lanosterol, dihydrolanosterol, phytosterol, cholic acid, and cholesteryl linoleate.

  Examples of waxes include candelilla wax, carnauba wax, rice wax, wax, beeswax, montan wax, ozokerite, ceresin, paraffin wax, microcrystalline wax, petrolatum, Fischer-Tropsch wax, polyethylene wax or ethylene / propylene copolymer. Etc.

  Examples of hydrocarbons include liquid paraffin (mineral oil), heavy liquid isoparaffin, light liquid isoparaffin, α-olefin oligomer, polyisobutene, hydrogenated polyisobutene, polybutene, squalane, olive-derived squalane, squalene, petrolatum or solid paraffin. Is mentioned.

  Examples of monoalcohol carboxylic acid esters include octyldodecyl myristate, hexyldecyl myristate, octyldodecyl isostearate, cetyl paritate, octyldodecyl palmitate, cetyl octoate, hexyldecyl octoate, isotridecyl isononanoate, and isononanoic acid Isononyl, octyl isononanoate, isotridecyl isononanoate, isodecyl neopentanoate, isotridecyl neopentanoate, isostearyl neopentanoate, octyldodecyl neodecanoate, oleyl oleate, octyldodecyl oleate, octyldodecyl ricinoleate, octyldodecyl lanolinate, dimethyloctanoic acid Hexyldecyl, octyldodecyl erucate, isostearic acid hydrogenated castor oil, olein Ethyl, avocado oil fatty acid ethyl, isopropyl myristate, isopropyl palmitate, octyl palmitate, isopropyl isostearate, lanolin fatty acid isopropyl, diethyl sebacate, diisopropyl sebacate, dioctyl sebacate, diisopropyl adipate, dibutyloctyl sebacate, adipic acid Examples include diisobutyl, dioctyl succinate or triethyl citrate.

  Examples of the oxyacid esters include cetyl lactate, diisostearyl malate, or monoisostearic acid hydrogenated castor oil.

  Examples of polyhydric alcohol fatty acid esters include glyceryl trioctanoate, glyceryl trioleate, glyceryl triisostearate, glyceryl diisostearate, glyceryl tri (caprylic acid / capric acid), tri (caprylic acid / capric acid / myristic acid / Stearic acid) glyceryl, hydrogenated rosin triglyceride (hydrogenated ester gum), rosin triglyceride (ester gum), glyceryl behenate, trimethylolpropane trioctanoate, trimethylolpropane triisostearate, neopentylglycol dioctanoate, dicaprin Neopentyl glycol acid, 2-butyl-2-ethyl-1,3-propanediol dioctanoate, propylene glycol dioleate, tetraoctanoic acid pen Erythrityl, hydrogenated rosin pentaerythrityl, triethylhexanoic acid ditrimethylolpropane, (isostearic acid / sebacic acid) ditrimethylolpropane, triethylhexanoic acid pentaerythrityl, (hydroxystearic acid / stearic acid / rosinic acid) dipentaerythrityl, diisostearic acid di Glyceryl, polyglyceryl tetraisostearate, polyglyceryl-10 nonaisostearate, deca (erucic acid / isostearic acid / ricinoleic acid) polyglyceryl-8, (hexyldecanoic acid / sebacic acid) diglyceryl oligoester, glycol distearate (ethylene glycol distearate) , Dineopentanoic acid 3-methyl-1,5-pentanediol or dineopentanoic acid 2,4-diethyl-1,5 Pentane diol, and the like.

  Examples of silicones include dimethicone (dimethylpolysiloxane), highly polymerized dimethicone (highly polymerized dimethylpolysiloxane), cyclomethicone (cyclic dimethylsiloxane, decamethylcyclopentasiloxane), phenyltrimethicone, diphenyldimethicone, phenyldimethicone, steer. Roxypropyldimethylamine, (aminoethylaminopropylmethicone / dimethicone) copolymer, dimethiconol, dimethiconol crosspolymer, silicone resin, silicone rubber, amino-modified silicone such as aminopropyldimethicone or amodimethicone, cationic modified silicone, dimethicone copolyol and other poly Ether-modified silicone, polyglycerin-modified silicone, sugar-modified silicone, carboxylic acid-modified silicone, phosphoric acid-modified silicone Corn, sulfuric acid modified silicone, alkyl modified silicone, fatty acid modified silicone, alkyl ether modified silicone, amino acid modified silicone, peptide modified silicone, fluorine modified silicone, cationic modified or polyether modified silicone, amino modified or polyether modified silicone, alkyl modified or Examples thereof include polyether-modified silicone or polysiloxane / oxyalkylene copolymer.

  Examples of the higher alcohols include cetanol, myristyl alcohol, oleyl alcohol, lauryl alcohol, cetostearyl alcohol, stearyl alcohol, aralkyl alcohol, behenyl alcohol, jojoba alcohol, chimyl alcohol, ceralkyl alcohol, batyl alcohol, hexyl decanol, and isostearyl. Alcohol, 2-octyldodecanol, dimer diol, etc. are mentioned.

  Examples of higher fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, behenic acid, undecylenic acid, 12-hydroxystearic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, erucic acid, Examples include docosahexaenoic acid, eicosapentaenoic acid, isohexadecanoic acid, anteisohenicosanoic acid, long-chain branched fatty acid, dimer acid, or hydrogenated dimer acid.

  Examples of the fluorinated oils include perfluorodecane, perfluorooctane, and perfluoropolyether.

  Examples of the (polyhydric) alcohol include ethanol, isopropanol, glycerin, propylene glycol, 1,3-butylene glycol, and polyethylene glycol.

  Other bases are not particularly limited, but include tapes (reservoir type, matrix type, etc.) such as plasters or plasters, patches such as poultices, patches, microneedles, ointments, liniments. And lotion preparations, sprays such as aerosols and pump sprays, creams, gels, eye drops, eye ointments, nasal drops, suppositories, rectal semisolids, or enemas And the like used in the above.

2.2. Other additive components The preparation of the present invention may contain other additive components depending on the dosage form, purpose of use, and the like.

  Additive components are not particularly limited, but include excipients, colorants, lubricants, binders, emulsifiers, thickeners, wetting agents, stabilizers, preservatives, solvents, solubilizers, suspending agents, Examples include a buffer, a pH adjuster, a gelling agent, an adhesive, an antioxidant, an absorption accelerator, an irritation relaxation agent, a preservative, a chelating agent, and a dispersing agent.

  In addition, in the preparation of the present invention, when the base phase is not included, the particles are included, or when the base phase is included, the base phase in which the particles are included (hereinafter collectively referred to as “particles”). It may be referred to as “containing basic component”), and may be dispersed in other components. In this case, the preparation of the present invention is provided by mixing and dispersing or emulsifying particles or particle-containing basic components in a component in which particles or particle-containing basic components are not completely dissolved.

  It can be appropriately selected depending on the dosage form, and is not particularly limited. For example, tapes such as plasters and plasters (reservoir type, matrix type, etc.), patches, patches, microneedles, and other ointments , External liquids such as liniments and lotions, sprays such as external aerosols and pump sprays, creams, gels, eye drops, eye ointments, nose drops, suppositories, rectal semi-solids or injections In order to provide it as an intestinal agent or the like, particles or particle-containing basic components can be mixed and dispersed or emulsified in a base or the like used in each dosage form.

3. Method for Producing Particles and Formulations The particles of the present invention are not particularly limited. For example, the particles can be produced by a method including a step of drying a W / O emulsion containing an active ingredient in an aqueous phase.

  The W / O emulsion is not particularly limited as long as it is a so-called water-in-oil emulsion, specifically, an emulsion in which droplets of an aqueous solvent are dispersed in an oily solvent.

  The W / O emulsion containing the active ingredient in the aqueous phase is a mixture of an aqueous solvent such as water or an aqueous buffer solution containing the active ingredient and an oily solvent such as cyclohexane, hexane, or toluene containing the surfactant. Can be obtained. The aqueous solvent containing the active ingredient may contain an additive ingredient such as a stabilizer, an absorption promoter or an irritation reducing agent, if necessary, in addition to the active ingredient. The oil-based solvent containing the surfactant may contain additional components such as an irritation reducing agent, an analgesic agent, an absorption accelerator, or a stabilizer, as necessary, in addition to the active ingredient.

  The mixing method is not particularly limited as long as it is a method capable of forming a W / O emulsion, and examples thereof include stirring with a homogenizer or the like. The conditions at the time of a homogenizer stirring are about 5000-50000 rpm, for example, Preferably, it is about 10000-30000 rpm.

  The weight ratio of the active ingredient to the surfactant in the W / O emulsion (active ingredient weight: surfactant weight) is not particularly limited, and can be, for example, 1: 3 to 1: 100. From the viewpoint that the effects of the present invention can be more reliably exhibited, the weight ratio is preferably 1: 5 to 1: 100, more preferably 1: 5 to 1:70, and 1: 5 to 1. : 50 is more preferable, 1: 5 to 1:40 is particularly preferable, and 1: 5 to 1:35 is most preferable.

  The method for drying the W / O emulsion is not particularly limited as long as it is a method capable of removing the solvent (aqueous solvent and oily solvent) in the emulsion, and examples thereof include freeze drying and drying under reduced pressure. Preferably, lyophilization is used.

  Thus, since the manufacturing method of this embodiment includes the process of drying the W / O emulsion which contains an active ingredient in an aqueous phase, the active ingredient containing particle | grains whose particle main body is solid can be obtained. Since the particle body is solid, the stability in the above-described base is further improved. Moreover, the active ingredient containing particle | grains whose particle main body is solid are disperse | distributed in the base phase which is an oil phase, and the formulation which has a structure of S / O (Solid in Oil) type | mold can be formed.

  Although not intended to be limited in interpretation, the particle affinity index X is determined by the weight ratio between the active ingredient and the surfactant during particle formation, the octanol water partition coefficient of the active ingredient, the type of salt of the active ingredient, or When the active ingredient is a free form, it is considered that it may vary depending on the type of salt that it can form. For example, if the weight ratio between the active ingredient and the surfactant is too low or too high, the affinity index X tends to be low. However, the appropriate weight ratio varies depending on the active ingredient. The active ingredient is an acid salt or a free form capable of forming an acid salt, or a desired affinity index X is easily obtained if the octanol water partition coefficient is in an appropriate range. On the other hand, other than this case, for example, by appropriately setting conditions such as adjusting the weight ratio to an appropriate range or adding an appropriate additive to the particles, a desired affinity index X can be obtained. It is possible to obtain the particles of the invention shown.

  The particles of the present invention may be used as they are, but may be used by dispersing in the above-mentioned base or the like.

  Moreover, a formulation can be manufactured, for example with a solution coating method using the particle | grains of this invention. In the solution coating method, in addition to the particles and the base of the present invention, a solvent such as hexane, toluene, or ethyl acetate is used so that an additional component such as an absorption accelerator, a thickener, or a gelling agent is added in a predetermined ratio as desired. And stir to prepare a homogeneous solution. The solid content concentration in the solution is preferably 10 to 80% by weight, more preferably 20 to 60% by weight.

  Next, the said solution containing each component is uniformly apply | coated on release liners, such as a polyester film etc. which were silicone-treated using coating machines, such as a knife coater, a comma coater, or a reverse coater. After application, the drug-containing layer is completed by drying, and an absorbent preparation can be obtained by laminating a support on the drug-containing layer. Depending on the type of the support, the release liner may be laminated on the surface of the drug-containing layer after the drug-containing layer is formed on the support.

  As another method, for example, additives such as a base, an absorption accelerator, a stabilizer, a thickener, and a gelling agent are added to and mixed with the particles of the present invention as necessary. Depending on the application, natural fabric members such as gauze or absorbent cotton, synthetic fiber fabric members such as polyester or polyethylene, or a combination of these appropriately processed into woven or non-woven fabrics, laminated or impregnated permeable membranes, etc. And hold it. Furthermore, it can be used by covering with an adhesive cover material or the like.

  The thus obtained absorption preparation is appropriately cut into a shape such as an oval, a circle, a square, or a rectangle according to the intended use. Moreover, you may provide an adhesive phase etc. in the periphery as needed.

  EXAMPLES The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.

Example 1; (active ingredient: surfactant = 1: 10)
0.1 g of octreotide acetate (manufactured by BACHEM, octanol water partition coefficient: 0.1) was dissolved in 40 g of pure water, and sucrose erucic acid ester (manufactured by Mitsubishi Chemical Foods, trade name “ER-290”). ”, HLB value: 2) A solution of 1.0 g in 80 g of cyclohexane was added and stirred with a homogenizer (10,000 rpm). After that, the particles were freeze-dried for 2 days to obtain particles containing an active ingredient in the particle body and a surfactant in the coating layer. The number average particle size calculated by a dynamic light scattering method (Spectris, product number “Zetasizer Nano S”) was 100 nm.

Example 2; (active ingredient: surfactant = 1: 15)
Particles were obtained in the same manner as in Example 1 except that the amount of sucrose erucic acid ester was 1.5 g.

Comparative Example 1 (active ingredient: surfactant = 1: 50)
Instead of octreotide acetate, risedronate-sodium 2.5 hydrate (manufactured by Tokyo Chemical Industry Co., Ltd., octanol water partition coefficient: -5.0) was used, and the amount of sucrose erucic acid ester was 5.0 g. Except for this, particles were obtained in the same manner as in Example 1.

Comparative Example 2 (active ingredient: surfactant = 1: 100)
Particles were obtained in the same manner as in Comparative Example 1 except that the amount of sucrose erucic acid ester was 10 g.

Comparative Example 3 (active ingredient: surfactant = 1: 30)
Example 1 except that memantine hydrochloride (manufactured by Tokyo Chemical Industry Co., Ltd., octanol water partition coefficient: 0.3) was used instead of octreotide acetate, and the amount of sucrose erucic acid ester was 3.0 g. Particles were obtained in the same manner.

Comparative Example 4 (active ingredient: surfactant = 1: 50)
Particles were obtained in the same manner as in Comparative Example 3 except that the amount of sucrose erucic acid ester was 5.0 g.

Comparative Example 5 (active ingredient: surfactant = 1: 100)
Particles were obtained in the same manner as in Comparative Example 3 except that the amount of sucrose erucic acid ester was 10.0 g.

Test Example 1: Small-angle X-ray scattering analysis Surfactant (sucrose erucic acid ester (ER-290) used for the preparation of the particles of Examples and Comparative Examples and the particles of Examples and Comparative Examples by the small-angle X-ray scattering method )) Was analyzed. The analysis conditions are as follows.

X-ray source: Research Center for High-Intensity Optical Science, SPring-8, Beamline BL40B2
Camera length: 1.25m
X-ray wavelength: 0.71 mm
Beam size (full width at half maximum): 0.2 mm x 0.2 mm
Measurement time: 10 to 60 seconds / 1 sample Measurement temperature: 25 ° C.

Based on the obtained data, a scattering profile was created in which the horizontal axis represents the size of the scattering vector q (nm ⁻¹ ) and the vertical axis represents the scattering intensity I. Note that q = (4π / λ) sin (θ / 2) (λ is the wavelength of X-rays and θ is the scattering angle). The scattering profile is shown in FIGS.

Further, in the scattering profile of the particles, the scattering vector q is ^{1. in} the range of 1.0 to 3.0 (nm ⁻¹ ). A value obtained by subtracting the scattering vector q at the maximum value in the range of ^{0 to} 3.0 (nm ⁻¹ ) was calculated as the affinity index X. The affinity index X is shown in Table 1.

Test Example 2 Hairless Rat Skin Permeability Test Hairless rat skin (Japan SLC, HWY / Slc, extracted from 8 weeks old) was set in a drug skin permeation test cell (FIG. 4). The particles of Examples and Comparative Examples or active ingredients (octreotide acetate, rivastigmine, risedronate-sodium 2.5 hydrate, memantine hydrochloride, loxoprofen sodium, and diclofenac sodium) are added to the upper part of the apparatus. In addition to Plastic Base (Taisho Pharmaceutical Co., Ltd.) so as to be 1% by weight based on the total weight of the formulation, 0.3 g (about 3.14 cm ² ) of the formulation produced by mixing and dispersing was applied. In the lower receptor layer, NaH ₂ PO ₄ in distilled water is 5 × 10 ⁻⁴ M, Na ₂ HPO ₄ is 2 × 10 ⁻⁴ M, NaCl is 1.5 × 10 ⁻⁴ M, gentamicin sulfate (Wako Pure Chemical Industries, Ltd.). A buffer solution prepared by adjusting the pH of the solution containing 10 ppm of G1658) manufactured by Yakuhin Co. to pH 7.2 with NaOH was added. Moreover, the apparatus was installed in the thermostat kept at 32 degreeC after the test start. 48 hours after the start of the test, 1 ml of the liquid in the tank was collected from the lower receptor layer, and immediately after that, 1 ml of the same composition was replenished. Methanol was added to each collected receptor liquid sample to extract eluted lipids and the like, followed by centrifugation. After centrifugation, the active ingredient concentration in the supernatant was quantified by high performance liquid chromatography (HPLC) (apparatus: system controller; manufactured by Shimadzu Corporation, product number “CBM-20A”, liquid feeding unit; manufactured by Shimadzu Corporation, Product number “LC-20AD”, column oven: manufactured by Shimadzu Corporation, product number “CTO-20A”, detector: manufactured by Shimadzu Corporation, product number “SPD-20A”, detection wavelength: 271 nm, column used: Thermoscientific, product Name “Hypersi GOLD”, 150 × 4.6 mm, 3 μm).

Based on the calculated cumulative permeation amount after 48 hours (μg / cm ² ), the magnification (magnification permeation rate magnification) at which the cumulative permeation amount was changed by atomizing the active ingredient was determined. Specifically, [the cumulative permeation amount after 48 hours when the particles are applied (μg / cm ² )] is [the cumulative permeation amount after 48 hours when only the active ingredient is applied (μg / cm ² )]. The value obtained by dividing was calculated. The results are shown in Table 1 and FIG. In FIG. 5, black circles indicate the plots of the examples, and black triangles indicate the plots of the comparative examples.

  As shown in Table 1 and FIG. 5, the particles of the comparative example (affinity index X ≦ 0.05) did not improve the skin permeability due to the formation of the active ingredient (magnification permeation rate magnification ≦ 2). ). In contrast, the particles of the example (affinity index X> 0.05) had improved skin permeability (particulate permeation magnification> 2) due to the formation of active ingredients.

DESCRIPTION OF SYMBOLS 1 ... Parafilm 2 ... Skin 3 ... Formulation 4 ... Receptor solution (pH = 7.2 phosphate buffer solution)
5 ... Stir bar

Claims (8)

A particle body containing an active ingredient;
A coating layer that covers at least a part of the surface of the particle body and contains a surfactant;
The particle body is solid;
An active ingredient-containing particle having an affinity index X represented by the following formula (1) in a range of 0.05 <X <0.2.
X = S ₀ −S ₁ (1)
Wherein (1), S _1, in a scattering profile obtained by small-angle X-ray scattering at measurement temperature 25 ° C. of the active ingredient-containing particles, indicates the scattering vector q at the maximum value of scattering intensity (nm ^-1) , S ₀ represents a scattering vector q (nm ⁻¹ ) at the maximum value of the scattering intensity in a scattering profile obtained by small-angle X-ray scattering at a measurement temperature of 25 ° C. of the surfactant. ]   The active ingredient-containing particle according to claim 1, wherein the particle body is a core part, the coating layer is a shell part, and has a core-shell structure. The active ingredient-containing particles according to claim 1 or 2, wherein a scattering vector q at the maximum value of the active ingredient-containing particles and the surfactant is in a range of 1.0 to 3.0 nm- ¹ .   The formulation containing the active ingredient containing particle | grains of any one of Claims 1-3.   The preparation according to claim 4, wherein the weight ratio of the active ingredient to the surfactant (active ingredient weight: surfactant weight) is in the range of 1: 5 to 1: 100.   An external preparation comprising the preparation according to claim 4 or 5.   Cosmetics comprising the preparation according to claim 4 or 5.   An injection comprising the preparation according to claim 4 or 5.

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